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Brain Penetration of the ROS1/ALK Inhibitor Lorlatinib Confirmed by PET

Brain Penetration of the ROS1/ALK Inhibitor Lorlatinib Confirmed by PET 11 18 The Massachusetts General Hospital Radiochemistry Program, in collaboration with Pfizer, has developed unique C and F- labeling strategies to synthesize isotopologs of lorlatinib (PF-06463922) which is undergoing phase III clinical trial investigations for treatment of non-small-cell lung cancers with specific molecular alterations. A major goal in cancer therapeutics is to measure the concentrations of this drug in the brain metastases of patients with lung cancer, and penetration of the blood–brain barrier is important for optimal therapeutic outcomes. Our recent publication in Nature Communications employed radiolabeled lorlatinib and positron emission tomography (PET) studies in preclinical models including nonhuman primates (NHPs) that demonstrated high brain permeability of this compound. Our future work with radiolabeled lorlatinib will include advanced PET evaluations in rodent tumor models and normal NHPs with the goal of clinical translation. Keywords lorlatinib, positron emission tomography, carbon-11, fluorine-18, ALK, ROS1 We have recently published the application of unique radiochem- Fundamentally, there are 3 criteria that need to be measured, istry strategies to radiolabel the brain penetrant anticancer drug termed the “Three Pillars of Survival” by Morgan et al. Pillar lorlatinib (PF-06463922), which is undergoing phase I-III clini- 1, defined as “exposure at the target site of action,” is a core cal trial investigations for treatment of non-small-cell lung can- principle as without exposure one cannot achieve the subse- cers (NSCLC; http://clinicaltrials.gov/ct2/show/NCT01970865). quent 2 pillars, namely, target engagement through binding to Lorlatinib is a next-generation small molecule macrocyclic inhi- the pharmacological target (pillar 2) and downstream expres- bitor of both the orphan receptor tyrosine kinase c-ros oncogene sion of pharmacology (pillar 3). While direct measurement of 1 (ROS1) and anaplastic lymphoma kinase (ALK) and is the first pillar 1 can be difficult to perform, PET offers a way to achieve in class to show significant brain penetration. In addition to this if the drug candidate can be readily radiolabeled with an improvement in potency against both ALK and the various appropriate radionuclide in a manner that causes no structural mutants, lorlatinib was designed with improved permeability to changes. Overall, the utilization of PET imaging as a tool in cross the blood–brain barrier (BBB), though in vivo data would be critical to confirm this, and to ensure continued investment in Division of Nuclear Medicine and Molecular Imaging, Massachusetts General the drug’s development. The Pfizer Oncology Team needed to Hospital (MGH) & Department of Radiology, Harvard Medical School, prove that lorlatinib had sufficient central nervous system (CNS) Boston, MA, USA exposure to target brain metastases. Our manuscript titled Advion, Inc, Ithaca, NY, USA “Synthesis and preliminary positron emission tomography (PET) Clinical and Translational Imaging, Worldwide Research and Development, 11 18 imaging of C- and F-isotopologs of the ROS1/ALK inhibitor Pfizer Inc, Cambridge, MA, USA Medicinal Sciences, Pfizer Inc, La Jolla, CA, USA lorlatinib in non-human primates” worked toward this goal Waterhouse Imaging and Biomarker Consultants, Chester, NH, USA through a multi-institutional collaboration among chemists with expertise in synthetic organic and medicinal chemistry, as well as Submitted: 01/09/2017. Revised: 07/09/2017. Accepted: 07/09/2017. radiochemistry and molecular imaging from Harvard Medical Corresponding Authors: School, Massachusetts General Hospital, and Pfizer. Neil Vasdev and Rikki N. Waterhouse, Massachusetts General Hospital, As novel drug candidates enter clinical testing, it is vital that Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. data are collected to demonstrate proof of mechanism. Emails: vasdev.neil@mgh.harvard.edu; wibc2016@gmail.com Creative Commons CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Molecular Imaging 11 18 Figure 1. Synthesis of (A) C- and (B) F-labeled isotopologs of lorlatinib. drug development has expanded over the past few decades the cerebellum exceeding a standardized uptake value of 2 at and has proved to be fruitful in confirming target exposure approximately 10 minutes postinjection. Regional uptake (pillar 1), optimization of drug scheduling, patient selection/ exhibited modest heterogeneity but was generally concordant stratification, and disease/treatment monitoring. with expected ALK distribution, with highest radioactivity Our primary aim is to measure the concentrations of lorla- concentrations in the cerebellum, frontal cortex, and thalamus; tinib in brain tumor lesions of patients with lung cancer and intermediate levels in other cortical gray matter; and lowest confirm its penetration across the BBB, which is considered to values in white matter. These PET imaging results support that be important for an optimal therapeutic outcome. Toward our lorlatinib crosses the BBB at sufficient concentrations to be goal of assessing the biodistribution and whole-body dosimetry potentially effective against brain metastases, per pillar 1. 11 18 of lorlatinib by PET, we prepared both C and F isotopologs In support of pillar 2, we sought to establish target engage- of lorlatinib (Figure 1). Carbon-11-labeled lorlatinib was rou- ment through binding to the pharmacological target. Herein, we tinely prepared with good radiochemical yields, and PET ima- assessed tumor uptake of [ C]lorlatinib in mice bearing sub- ging in nonhuman primates confirmed its high BBB cutaneous human H3122 (EML4-ALK positive) xenografts by permeability (vide infra). Novel radiolabeling strategies PET-CT imaging in conjunction with blocking studies. These including an automated multistep C-labeling process and a studies showed that the tumor uptake reached its plateau in spirocyclic iodonium ylide (SCIDY)-based radiofluorination approximately 30 to 60 minutes after injection of [ C]lorlati- were critical to implement the PET imaging studies when tra- nib (>2% ID/g) and co-injection with unlabeled lorlatinib 4,5 ditional labeling methods failed. In particular, our SCIDY resulted in significant decrease in the tumor uptake (<0.4% technology has been validated for other human PET imaging ID/g), thereby providing support of pillar 2. studies and is used by academic centers as well as the radio- The existence or progression of the cancer into the CNS is pharmaceutical industry to prepare isotopologs of lead drug associated with poorer prognoses for patients with NSCLC and molecules that were previously challenging to prepare. constitutes a true unmet medical need. In this age of increasing Imaging of C-radiolabeled lorlatinib in nonhuman pri- costs and time constraints of clinical trials, herein the case of mates provided unequivocal in vivo confirmation of the desired lorlatinib as with many other studies, a rigorously designed BBB permeability with rapid brain uptake (Figure 2). PET imaging study has proven to be an invaluable early clinical Peak-measured brain concentrations were locally high, with development tool in drug discovery and development. By Collier et al 3 Authors’ Note N.V. thanks Pfizer and the National Institute on Ageing of the NIH for funding (R01AG054473). S.H.L. is a recipient of an NIH career devel- opment award (DA038000) and an Early Career Award in Chemistry of Drug Abuse and Addiction (ECHEM, DA043507) from the National Institute on Drug Abuse. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no financial support for the research, author- ship, and/or publication of this article. References 1. Collier TL, Normandin MD, Stephenson NA, et al. Synthesis and 11 18 preliminary PET imaging of Cand F isotopologues of the ROS1/ALK inhibitor lorlatinib. Nat Commun. 2017;8:15761. 2. Johnson TW, Richardson PF, Bailey S, et al. Discovery of (10R)- 7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetra- hydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]- benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. JMed Chem. 2014;57(11):4720–4744. 3. Morgan P, Van Der Graaf PH, Arrowsmith J, et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and phar- macological principles toward improving phase II survival. Drug Discov Today. 2012;17(9-10):419–424. 4. Rotstein BH, Stephenson NA, Vasdev N, Liang SH. Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non- activated and hindered aromatics. Nat Commun. 2014;5:4365. 5. Rotstein BH, Wang L, Liu RY, et al. Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(III) ylides. Chem Sci. 2016;7(7): Figure 2. Top panels depict the representative PET imaging of 4407–4417. [ C]lorlatinib in rhesus macaque, including a time course from 10 to 25 minutes postinjection of the radiotracer. The corresponding 6. Stephenson NA, Holland JP, Kassenbrock A, et al. Iodonium regional time-activity curves (below) show the rapid uptake followed ylide–mediated radiofluorination of F-FPEB and validation for by fast washout of the radiotracer from normal brain tissues. human use. J Nucl Med. 2015;56(3):489–492. 7. Bernard-Gauthier V, Bailey JJ, Mossine AV, et al. A kinome- confirming pillar 1 and supporting pillar 2 through in vivo PET wide selective radiolabeled TrkB/C inhibitor for in vitro and in imaging studies, this symbiotic academic–industrial partner- vivo neuroimaging: synthesis, preclinical evaluation and first-in- ship has not only led to 2 novel PET radiotracers for an unpre- human. J Med Chem. 2017;60(16):6897–6910. cedented imaging target but also inspired the development of 8. Hicks JW, VanBrocklin HF, Wilson AA, Houle S, Vasdev N. new carbon-11 and fluorine-18 labeling methodologies. We Radiolabeled small molecule protein kinase inhibitors for ima- anticipate translating radiolabeled lorlatinib for PET clinical ging with PET or SPECT. Molecules. 2010;15(11):8260–8278. research studies in the near future. Given the excitement around 9. Holland JP, Cumming P, Vasdev N. PET of signal transduction potent and selective kinase inhibitors in drug development and pathways in cancer. J. Nucl Med. 2012;53(9):1333–1336. 7-10 related diagnostic radioimaging agents for kinase targets, 10. Holland JP, Cumming P, Vasdev N. PET radiopharmaceuticals we anticipate multiple first-in-human studies around unex- for probing enzymes in the brain. Am J Nucl Med Mol Imaging. plored kinase targets within the CNS. 2013;3(3):194–216. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular Imaging Pubmed Central

Brain Penetration of the ROS1/ALK Inhibitor Lorlatinib Confirmed by PET

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Pubmed Central
Copyright
© The Author(s) 2017
ISSN
1535-3508
eISSN
1536-0121
DOI
10.1177/1536012117736669
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Abstract

11 18 The Massachusetts General Hospital Radiochemistry Program, in collaboration with Pfizer, has developed unique C and F- labeling strategies to synthesize isotopologs of lorlatinib (PF-06463922) which is undergoing phase III clinical trial investigations for treatment of non-small-cell lung cancers with specific molecular alterations. A major goal in cancer therapeutics is to measure the concentrations of this drug in the brain metastases of patients with lung cancer, and penetration of the blood–brain barrier is important for optimal therapeutic outcomes. Our recent publication in Nature Communications employed radiolabeled lorlatinib and positron emission tomography (PET) studies in preclinical models including nonhuman primates (NHPs) that demonstrated high brain permeability of this compound. Our future work with radiolabeled lorlatinib will include advanced PET evaluations in rodent tumor models and normal NHPs with the goal of clinical translation. Keywords lorlatinib, positron emission tomography, carbon-11, fluorine-18, ALK, ROS1 We have recently published the application of unique radiochem- Fundamentally, there are 3 criteria that need to be measured, istry strategies to radiolabel the brain penetrant anticancer drug termed the “Three Pillars of Survival” by Morgan et al. Pillar lorlatinib (PF-06463922), which is undergoing phase I-III clini- 1, defined as “exposure at the target site of action,” is a core cal trial investigations for treatment of non-small-cell lung can- principle as without exposure one cannot achieve the subse- cers (NSCLC; http://clinicaltrials.gov/ct2/show/NCT01970865). quent 2 pillars, namely, target engagement through binding to Lorlatinib is a next-generation small molecule macrocyclic inhi- the pharmacological target (pillar 2) and downstream expres- bitor of both the orphan receptor tyrosine kinase c-ros oncogene sion of pharmacology (pillar 3). While direct measurement of 1 (ROS1) and anaplastic lymphoma kinase (ALK) and is the first pillar 1 can be difficult to perform, PET offers a way to achieve in class to show significant brain penetration. In addition to this if the drug candidate can be readily radiolabeled with an improvement in potency against both ALK and the various appropriate radionuclide in a manner that causes no structural mutants, lorlatinib was designed with improved permeability to changes. Overall, the utilization of PET imaging as a tool in cross the blood–brain barrier (BBB), though in vivo data would be critical to confirm this, and to ensure continued investment in Division of Nuclear Medicine and Molecular Imaging, Massachusetts General the drug’s development. The Pfizer Oncology Team needed to Hospital (MGH) & Department of Radiology, Harvard Medical School, prove that lorlatinib had sufficient central nervous system (CNS) Boston, MA, USA exposure to target brain metastases. Our manuscript titled Advion, Inc, Ithaca, NY, USA “Synthesis and preliminary positron emission tomography (PET) Clinical and Translational Imaging, Worldwide Research and Development, 11 18 imaging of C- and F-isotopologs of the ROS1/ALK inhibitor Pfizer Inc, Cambridge, MA, USA Medicinal Sciences, Pfizer Inc, La Jolla, CA, USA lorlatinib in non-human primates” worked toward this goal Waterhouse Imaging and Biomarker Consultants, Chester, NH, USA through a multi-institutional collaboration among chemists with expertise in synthetic organic and medicinal chemistry, as well as Submitted: 01/09/2017. Revised: 07/09/2017. Accepted: 07/09/2017. radiochemistry and molecular imaging from Harvard Medical Corresponding Authors: School, Massachusetts General Hospital, and Pfizer. Neil Vasdev and Rikki N. Waterhouse, Massachusetts General Hospital, As novel drug candidates enter clinical testing, it is vital that Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. data are collected to demonstrate proof of mechanism. Emails: vasdev.neil@mgh.harvard.edu; wibc2016@gmail.com Creative Commons CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Molecular Imaging 11 18 Figure 1. Synthesis of (A) C- and (B) F-labeled isotopologs of lorlatinib. drug development has expanded over the past few decades the cerebellum exceeding a standardized uptake value of 2 at and has proved to be fruitful in confirming target exposure approximately 10 minutes postinjection. Regional uptake (pillar 1), optimization of drug scheduling, patient selection/ exhibited modest heterogeneity but was generally concordant stratification, and disease/treatment monitoring. with expected ALK distribution, with highest radioactivity Our primary aim is to measure the concentrations of lorla- concentrations in the cerebellum, frontal cortex, and thalamus; tinib in brain tumor lesions of patients with lung cancer and intermediate levels in other cortical gray matter; and lowest confirm its penetration across the BBB, which is considered to values in white matter. These PET imaging results support that be important for an optimal therapeutic outcome. Toward our lorlatinib crosses the BBB at sufficient concentrations to be goal of assessing the biodistribution and whole-body dosimetry potentially effective against brain metastases, per pillar 1. 11 18 of lorlatinib by PET, we prepared both C and F isotopologs In support of pillar 2, we sought to establish target engage- of lorlatinib (Figure 1). Carbon-11-labeled lorlatinib was rou- ment through binding to the pharmacological target. Herein, we tinely prepared with good radiochemical yields, and PET ima- assessed tumor uptake of [ C]lorlatinib in mice bearing sub- ging in nonhuman primates confirmed its high BBB cutaneous human H3122 (EML4-ALK positive) xenografts by permeability (vide infra). Novel radiolabeling strategies PET-CT imaging in conjunction with blocking studies. These including an automated multistep C-labeling process and a studies showed that the tumor uptake reached its plateau in spirocyclic iodonium ylide (SCIDY)-based radiofluorination approximately 30 to 60 minutes after injection of [ C]lorlati- were critical to implement the PET imaging studies when tra- nib (>2% ID/g) and co-injection with unlabeled lorlatinib 4,5 ditional labeling methods failed. In particular, our SCIDY resulted in significant decrease in the tumor uptake (<0.4% technology has been validated for other human PET imaging ID/g), thereby providing support of pillar 2. studies and is used by academic centers as well as the radio- The existence or progression of the cancer into the CNS is pharmaceutical industry to prepare isotopologs of lead drug associated with poorer prognoses for patients with NSCLC and molecules that were previously challenging to prepare. constitutes a true unmet medical need. In this age of increasing Imaging of C-radiolabeled lorlatinib in nonhuman pri- costs and time constraints of clinical trials, herein the case of mates provided unequivocal in vivo confirmation of the desired lorlatinib as with many other studies, a rigorously designed BBB permeability with rapid brain uptake (Figure 2). PET imaging study has proven to be an invaluable early clinical Peak-measured brain concentrations were locally high, with development tool in drug discovery and development. By Collier et al 3 Authors’ Note N.V. thanks Pfizer and the National Institute on Ageing of the NIH for funding (R01AG054473). S.H.L. is a recipient of an NIH career devel- opment award (DA038000) and an Early Career Award in Chemistry of Drug Abuse and Addiction (ECHEM, DA043507) from the National Institute on Drug Abuse. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no financial support for the research, author- ship, and/or publication of this article. References 1. Collier TL, Normandin MD, Stephenson NA, et al. Synthesis and 11 18 preliminary PET imaging of Cand F isotopologues of the ROS1/ALK inhibitor lorlatinib. Nat Commun. 2017;8:15761. 2. Johnson TW, Richardson PF, Bailey S, et al. Discovery of (10R)- 7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetra- hydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]- benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. JMed Chem. 2014;57(11):4720–4744. 3. Morgan P, Van Der Graaf PH, Arrowsmith J, et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and phar- macological principles toward improving phase II survival. Drug Discov Today. 2012;17(9-10):419–424. 4. Rotstein BH, Stephenson NA, Vasdev N, Liang SH. Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non- activated and hindered aromatics. Nat Commun. 2014;5:4365. 5. Rotstein BH, Wang L, Liu RY, et al. Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(III) ylides. Chem Sci. 2016;7(7): Figure 2. Top panels depict the representative PET imaging of 4407–4417. [ C]lorlatinib in rhesus macaque, including a time course from 10 to 25 minutes postinjection of the radiotracer. The corresponding 6. Stephenson NA, Holland JP, Kassenbrock A, et al. Iodonium regional time-activity curves (below) show the rapid uptake followed ylide–mediated radiofluorination of F-FPEB and validation for by fast washout of the radiotracer from normal brain tissues. human use. J Nucl Med. 2015;56(3):489–492. 7. Bernard-Gauthier V, Bailey JJ, Mossine AV, et al. A kinome- confirming pillar 1 and supporting pillar 2 through in vivo PET wide selective radiolabeled TrkB/C inhibitor for in vitro and in imaging studies, this symbiotic academic–industrial partner- vivo neuroimaging: synthesis, preclinical evaluation and first-in- ship has not only led to 2 novel PET radiotracers for an unpre- human. J Med Chem. 2017;60(16):6897–6910. cedented imaging target but also inspired the development of 8. Hicks JW, VanBrocklin HF, Wilson AA, Houle S, Vasdev N. new carbon-11 and fluorine-18 labeling methodologies. We Radiolabeled small molecule protein kinase inhibitors for ima- anticipate translating radiolabeled lorlatinib for PET clinical ging with PET or SPECT. Molecules. 2010;15(11):8260–8278. research studies in the near future. Given the excitement around 9. Holland JP, Cumming P, Vasdev N. PET of signal transduction potent and selective kinase inhibitors in drug development and pathways in cancer. J. Nucl Med. 2012;53(9):1333–1336. 7-10 related diagnostic radioimaging agents for kinase targets, 10. Holland JP, Cumming P, Vasdev N. PET radiopharmaceuticals we anticipate multiple first-in-human studies around unex- for probing enzymes in the brain. Am J Nucl Med Mol Imaging. plored kinase targets within the CNS. 2013;3(3):194–216.

Journal

Molecular ImagingPubmed Central

Published: Oct 25, 2017

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